Autosomal dominant polycystic kidney disease (ADPKD): The role of Aurora kinase A (AURKA), NEDD9 and SRC in renal cystogenesis
Final Report Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is a progressive genetic syndrome with an incidence of 1:500 in the population, arising from inherited mutations in PKD1 or PKD2. Symptoms typically manifest at middle age, with kidney function increasingly impaired and approximately one half of PKD patients progressing to end stage renal disease as a consequence of cystic remodeling of the kidney. In this project we show that genetic ablation of Nedd9 significantly promotes cyst formation in a conditional Pkd1-/- mouse model. Assessment of multiple cyst-associated phenotypes and signaling pathways indicates that while a Nedd9 null genotype has many effects, the most consistent explanation for its action in cystogenesis is in selectively enhancing the activation of SRC, ERK, and the mTOR effector S6 in the context of a mutated Pkd1 gene. The abnormal activation of those and other candidates is known to be associated with cyst progression and some mediators, including SRC and mTOR, have been successfully targeted in preclinical PKD studies, while clinical studies were less successful. As an alternative approach, we noted that many candidates we observe, through network construction, to be associated with PKD are regulated by heat shock protein 90 (HSP90). We hypothesized that inhibitors of the HSP90 chaperone protein are broadly active in limiting cyst growth and improving kidney function based on simultaneous inhibition of multiple proteins supporting progressive growth of cysts. To test our hypothesis we utilized STA-2842, a novel highly specific inhibitor of HSP90, in an adult Pkd1-/- mouse model, with a renal phenotype resembling human ADPKD. We found that STA-2842 significantly slowed down cyst progression both at early and late stages of cyst development. This was accompanied by HSP70 induction and reduced activity of HSP90 clients and their effector, ERK, biomarkers for HSP90 inhibition. Further, STA-2842 treatment downregulated a broad range of HSP90 clients and effectors that mediate the pathological changes that occur in ADPKD in primary kidney cells. Strikingly, elevation of HSP90 was particularly observed in the epithelial cells lining dilated tubules and renal cysts both in Pkd1-/- mice and similarly in human kidney cysts obtained from PKD patients. These results provide an initial justification for evaluating HSP90 inhibitors as therapeutic agents for ADPKD.
Publications
- Cilia and cilia-associated proteins in cancer. Drug Discov Today: Dis Mech (2013) [Epub ahead of print]
Seeger-Nukpezah T, Little JL, Serzhanova V, Golemis EA
(See online at https://dx.doi.org/10.1016/j.ddmec.2013.03.004) - Inhibiting the HSP90 chaperone slows cyst growth in a mouse model of autosomal dominant polycystic kidney disease. PNAS. 2013; 110(31): 12786-91
Seeger-Nukpezah T, Proia DA, Egleston BL, Nikonova AS, Kent T, Cai KQ, Hensley HH, Ying W, Chimmanamada D, Serebriiskii IG, Golemis EA
